tbuckley/cabot-search huggingface dataset:
Impact of P-gp and BCRP on pulmonary drug disposition assessed by PET imaging in rats
Authors: Severin Mairinger, Irene Hernández-Lozano, Thomas Filip, Michael Sauberer, Mathilde Löbsch, Johann Stanek, Thomas Wanek, Johannes A. Sake, Thomas Pekar, Carsten Ehrhardt, Oliver Langer
Journal: Journal of Controlled Release (2022)

P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) are two efflux transporters which are expressed in the apical (i.e. airway lumen-facing) membranes of lung epithelial cells. To assess the influence of P-gp and BCRP on the pulmonary disposition of inhaled drugs, we performed positron emission tomography (PET) imaging in rats after intratracheal aerosolization of two model P-gp/BCRP substrate radiotracers (i.e. [11C]erlotinib and [11C]tariquidar). We studied rat groups in which both transporters were active (i.e. wild-type rats), either of the two transporters was inactive (Abcb1a/b(−/−) and Abcg2(−/−) rats) or both transporters were inactive (Abcg2(−/−) rats in which pulmonary P-gp activity was inhibited by treatment with unlabeled tariquidar). PET-measured lung distribution data were compared with brain-to-plasma radioactivity concentration ratios measured in a gamma counter at the end of the PET scan. For [11C]erlotinib, lung exposure (AUClungs) was moderately but not significantly increased in Abcb1a/b(−/−) rats (1.6-fold) and Abcg2(−/−) rats (1.5-fold), and markedly (3.6-fold, p < 0.0001) increased in tariquidar-treated Abcg2(−/−) rats, compared to wild-type rats. Similarly, the brain uptake of [11C]erlotinib was substantially (4.5-fold, p < 0.0001) increased when both P-gp and BCRP activities were impaired. For [11C]tariquidar, differences in AUClungs between groups pointed into a similar direction as for [11C]erlotinib, but were less pronounced and lacked statistical significance. Our study demonstrates functional P-gp and BCRP activity in vivo in the lungs and further suggests functional redundancy between P-gp and BCRP in limiting the pulmonary uptake of a model P-gp/BCRP substrate, analogous to the blood-brain barrier. Our results suggest that pulmonary efflux transporters are important for the efficacy and safety of inhaled drugs and that their modulation may be exploited in order to improve the pharmacokinetic and pharmacodynamic performance of pulmonary delivered drugs.
Toward a base-resolution panorama of the in vivo impact of cytosine methylation on transcription factor binding
Authors: Aldo Hernandez-Corchado, Hamed S. Najafabadi
Journal: Genome biology (2022)

While methylation of CpG dinucleotides is traditionally considered antagonistic to the DNA-binding activity of most transcription factors (TFs), recent in vitro studies have revealed a more complex picture, suggesting that over a third of TFs may preferentially bind to methylated sequences. Expanding these in vitro observations to in vivo TF binding preferences is challenging since the effect of methylation of individual CpG sites cannot be easily isolated from the confounding effects of DNA accessibility and regional DNA methylation. Thus, in vivo methylation preferences of most TFs remain uncharacterized.
Interacting with others while reacting to the environment
Authors: Ilan Fischer, Simon A. Levin, Daniel I. Rubenstein, Shacked Avrashi, Lior Givon, Tomer Oz
Journal: Behavioral and Brain Sciences (2022)

Abstract Here, we revise Pietraszewski's model of groups by assigning participant pairs with two triplets, denoting: (1) the type of game that models the interaction, (2) its critical switching point between alternatives (i.e., the game's similarity threshold), and (3) the perception of strategic similarity with the opponent. These triplets provide a set of primitives that accounts for individuals' strategic motivations and observed behaviors.
Baseline and post-treatment biomarkers of resistance to anti-PD-1 therapy in acral and mucosal melanoma: an observational study
Authors: Irene M. Shui, Xiao Qiao Liu, Qing Zhao, Seung Tae Kim, Yuan Sun, Jennifer H. Yearley, Tasmiah Choudhury, Andrea L. Webber, Clemens Krepler, Razvan Cristescu, Jeeyun Lee
Journal: Journal for ImmunoTherapy of Cancer (2022)

Immunotherapies targeting programmed cell death-1 (PD-1) and its ligands have improved clinical outcomes for advanced melanoma. However, many tumors exhibit primary resistance or acquire secondary resistance after an initial positive response. The mechanisms of resistance are not well understood, and no validated predictive biomarkers are available. This exploratory study aimed to characterize baseline differences and molecular changes arising during treatment in acral and mucosal melanomas that exhibited primary or secondary resistance to anti-PD-1 monotherapy.This was an observational retrospective study of 124 patients who had been treated for metastatic acral or mucosal melanoma with anti-PD-1 monotherapy. Tumor samples were collected at baseline (all patients) and post-treatment (resistant tumors only) and were assayed by immunohistochemistry, whole-exome sequencing, and RNA sequencing.At baseline, more non-progressor than resistant tumors exhibited expression of PD-L1, immune cell infiltration, and high tumor mutational burden (TMB); baseline PD-L1 expression was also more common in secondary-resistant than in primary-resistant tumors as well as in late versus early secondary-resistant tumors. Non-progressor tumors also had higher median baseline expression of an 18-gene T cell-inflamed gene expression profile (TcellinfGEP). Among resistant tumors, the proportion of PD-L1-positive melanomas and the expression of the TcellinfGEP mRNA signature increased during treatment, while the expression of mRNA signatures related to WNT and INFA1 signaling decreased. There was evidence for greater changes from baseline in secondary-resistant versus primary-resistant tumors for some markers, including expression of RAS-related and WNT-related mRNA signatures and density of CD11c+ and FOXP3+ T cells. Greater changes in CD11c+ cell density were observed in early compared with late secondary-resistant tumors.Our findings suggest that TcellinfGEP and PD-L1 expression, TMB, immune cell infiltration, and RAS and WNT signaling warrant further investigation as potential mechanisms and/or biomarkers of anti-PD-1 therapy resistance in acral and mucosal melanomas. Confirmation of these findings in larger populations is needed.
Endovascular thrombectomy versus standard bridging thrombolytic with endovascular thrombectomy within 4·5 h of stroke onset: an open-label, blinded-endpoint, randomised non-inferiority trial
Authors: Peter J Mitchell, Bernard Yan, Leonid Churilov, Richard J Dowling, Steven J Bush, Andrew Bivard, Xiao Chuan Huo, Guoqing Wang, Shi Yong Zhang, Mai Duy Ton, Dennis J Cordato, Timothy J Kleinig, Henry Ma, Ronil V Chandra, Helen Brown, Bruce C V Campbell, Andrew K Cheung, Brendan Steinfort, Rebecca Scroop, Kendal Redmond, Ferdinand Miteff, Yan Liu, Dang Phuc Duc, Hal Rice, Mark W Parsons, Teddy Y Wu, Huy-Thang Nguyen, Geoffrey A Donnan, Zhong Rong Miao, Stephen M Davis, Patricia Desmond, Nawaf Yassi, Henry Zhao, Cameron Williams, Fana Alemseged, Felix C Ng, Vignan Yogendrakumar, Peter Bailey, Laetitia De Villiers, Thanh Phan, Tharani Thirugnanachandran, Winston Chong, Hamed Asadi, Lee Anne Slater, Nathan Manning, Jason Wenderoth, Alan McDougall, Cameron Williams, Cecilia Cappelen-Smith, Justin Whitley, Leon Edwards, Carlos Garcia Esperon, Neil Spratt, Elizabeth Pepper, Chris Levi, Ken Faulder, Timothy Harrington, Martin Krause, Michael Waters, John Fink, Gaoting Ma, Xiangpeng Shen, Xiangkong Song, Yonglei Gao, Nam Guangxian, Zaiyu Guo, Heliang Zhang, Hongxing Han, Hao Wang, Geng Liao, Zhenyu Zhang, Chaomao Li, Zhi Yang, Chuwei Cai, Chuming Huang, Yifan Hong
Journal: The Lancet (2022)
Group? What group? A computational model of the group needs a psychology of “us” (not “them”)
Authors: Janet Wiles, S. Alexander Haslam, Niklas K. Steffens, Jolanda Jetten
Journal: Behavioral and Brain Sciences (2022)

Abstract Groups are only real, and only serve as a basis for collective action, when their members perceive them to be real. For a computational model to have analytic fidelity and predictive validity it, therefore, needs to engage with the psychological reality of groups, their internal structure, and their structuring by (and of) the social context in which they function.
Imaging approaches and radiomics: toward a new era of ultraprecision radioimmunotherapy?
Authors: Roger Sun, Théophraste Henry, Adrien Laville, Alexandre Carré, Anthony Hamaoui, Sophie Bockel, Ines Chaffai, Antonin Levy, Cyrus Chargari, Charlotte Robert, Eric Deutsch
Journal: Journal for ImmunoTherapy of Cancer (2022)

Strong rationale and a growing number of preclinical and clinical studies support combining radiotherapy and immunotherapy to improve patient outcomes. However, several critical questions remain, such as the identification of patients who will benefit from immunotherapy and the identification of the best modalities of treatment to optimize patient response. Imaging biomarkers and radiomics have recently emerged as promising tools for the non-invasive assessment of the whole disease of the patient, allowing comprehensive analysis of the tumor microenvironment, the spatial heterogeneity of the disease and its temporal changes. This review presents the potential applications of medical imaging and the challenges to address, in order to help clinicians choose the optimal modalities of both radiotherapy and immunotherapy, to predict patient's outcomes and to assess response to these promising combinations.
Efficacy of anti-PD-1 and ipilimumab alone or in combination in acral melanoma
Authors: Prachi Bhave, Tasnia Ahmed, Serigne N Lo, Alexander Shoushtari, Anne Zaremba, Judith M Versluis, Joanna Mangana, Michael Weichenthal, Lu Si, Thierry Lesimple, Caroline Robert, Claudia Trojanello, Alexandre Wicky, Richard Heywood, Lena Tran, Kathleen Batty, Florentia Dimitriou, Anna Stansfeld, Clara Allayous, Julia K Schwarze, Meghan J Mooradian, Oliver Klein, Inderjit Mehmi, Rachel Roberts-Thomson, Andrea Maurichi, Hui-Ling Yeoh, Adnan Khattak, Lisa Zimmer, Christian U Blank, Egle Ramelyte, Katharina C Kähler, Severine Roy, Paolo A Ascierto, Olivier Michielin, Paul C Lorigan, Douglas B Johnson, Ruth Plummer, Celeste Lebbe, Bart Neyns, Ryan Sullivan, Omid Hamid, Mario Santinami, Grant A McArthur, Andrew M Haydon, Georgina V Long, Alexander M Menzies, Matteo S Carlino
Journal: Journal for ImmunoTherapy of Cancer (2022)

Acral melanoma is a rare melanoma subtype with poor prognosis. Importantly, these patients were not identified as a specific subgroup in the landmark melanoma trials involving ipilimumab and the anti-programmed cell death protein-1 (PD-1) agents nivolumab and pembrolizumab. There is therefore an absence of prospective clinical trial evidence regarding the efficacy of checkpoint inhibitors (CPIs) in this population. Acral melanoma has lower tumor mutation burden (TMB) than other cutaneous sites, and primary site is associated with differences in TMB. However the impact of this on the effectiveness of immune CPIs is unknown. We examined the efficacy of CPIs in acral melanoma, including by primary site.Patients with unresectable stage III/IV acral melanoma treated with CPI (anti-PD-1 and/or ipilimumab) were studied. Multivariable logistic and Cox regression analyses were conducted. Primary outcome was objective response rate (ORR); secondary outcomes were progression-free survival (PFS) and overall survival (OS).In total, 325 patients were included: 234 (72%) plantar, 69 (21%) subungual and 22 (7%) palmar primary sites. First CPI included: 184 (57%) anti-PD-1, 59 (18%) anti-PD-1/ipilimumab combination and 82 (25%) ipilimumab. ORR was significantly higher with initial anti-PD-1/ipilimumab compared with anti-PD-1 (43% vs 26%, HR 2.14, p=0.0004) and significantly lower with ipilimumab (15% vs 26%, HR 0.49, p=0.0016). Landmark PFS at 1 year was highest for anti-PD-1/ipilimumab at 34% (95% CI 24% to 49%), compared with 26% (95% CI 20% to 33%) with anti-PD-1 and 10% (95% CI 5% to 19%) with ipilimumab. Despite a trend for increased PFS, anti-PD-1/ipilimumab combination did not significantly improve PFS (HR 0.85, p=0.35) or OS over anti-PD-1 (HR 1.30, p=0.16), potentially due to subsequent therapies and high rates of acquired resistance. No outcome differences were found between primary sites.While the ORR to anti-PD-1/ipilimumab was significantly higher than anti-PD-1 and PFS numerically higher, in this retrospective cohort this benefit did not translate to improved OS. Future trials should specifically include patients with acral melanoma, to help determine the optimal management of this important melanoma subtype.
Quantification of <i>Aspergillus fumigatus</i> antigen Asp f 1 in airway tissue and allergic inflammation
Authors: Yui Miyabe, Hiroki Tomizawa, Hidekazu Saito, Toshiki Yamada, Kazuhiro Shiina, Koh Koizumi, Yohei Kawasaki, Shinsuke Suzuki, Mineyo Fukuchi, Shigeharu Ueki, Takashi Ebihara, Takechiyo Yamada
Journal: Allergy (2022)

Figure S1 Figure S2 Table S1 Appendix S1 Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Long-term outcomes of peroral endoscopic myotomy for achalasia: a systematic review and meta-analysis
Authors: Edoardo Vespa, Gaia Pellegatta, Viveksandeep T. Chandrasekar, Marco Spadaccini, Harsh Patel, Roberta Maselli, Piera A. Galtieri, Elisa Carlani, Prateek Sharma, Cesare Hassan, Alessandro Repici
Journal: Endoscopy (2022)

Background The long-term outcomes of esophageal peroral endoscopic myotomy (POEM) are still unknown. Methods We searched electronic databases (MEDLINE/PubMed, EMBASE, Scopus) for studies assessing outcomes after POEM for esophageal achalasia with a minimum median follow-up duration of 36 months. Pooled rates of clinical success and postoperative reflux were calculated and compared with the same values at 12/24/36 months when available. Subgroup analyses were performed to explore the interstudy heterogeneity. Results From 1528 initial records, 11 studies (2017–2021) were included. A total of 2342 patients (age 48.1 [SD 6.8] years; 50.1 % males) with a median follow-up of 48 months (interquartile range 45–60) were analyzed. The pooled clinical success rate was 87.3 % (95 %CI 83.6 %–91.0 %; I2 = 73.1 %). The symptomatic reflux pooled rate was 22.0 % (95 %CI 14.4 %–29.5 %; I2 = 92.7 %). Three cases of peptic strictures and one Barrett’s esophagus were reported. The pooled rate of severe adverse events was 1.5 % (95 %CI 0.5 %–2.5 %; I2 = 52.8 %). Conclusions Long-term clinical efficacy of POEM persisted in 87 % of patients with achalasia. Post-POEM symptomatic reflux remained stable over time. The risk for Barrett’s esophagus and peptic strictures appeared minimal.
Conciliation and meta-contrast are important for understanding how people assign group memberships during conflict situations
Authors: Mark Levine, Richard Philpot
Journal: Behavioral and Brain Sciences (2022)

Abstract Pietraszewski misrepresents both the nature of behaviour in conflict and the ability of psychology to theorise the relational properties of group designation. At the behavioural level, he focusses exclusively on “attack,” when consolation/care in conflict is equally present and important. At the theoretical level, he ignores existing psychological work on how group perception is shaped by the meta-contrast principle.
Zebrafish and inherited photoreceptor disease: Models and insights
Authors: Nicole C.L. Noel, W.Ted Allison, Ian M. MacDonald, Jennifer C. Hocking
Journal: Progress in Retinal and Eye Research (2022)

Photoreceptor dysfunctions and degenerative diseases are significant causes of vision loss in patients, with few effective treatments available. Targeted interventions to prevent or reverse photoreceptor-related vision loss are not possible without a thorough understanding of the underlying mechanism leading to disease, which is exceedingly difficult to accomplish in the human system. Cone diseases are particularly challenging to model, as some popular genetically modifiable model animals are nocturnal with a rod-dominant visual system and cones that have dissimilarities to human cones. As a result, cone diseases, which affect visual acuity, colour perception, and central vision in patients, are generally poorly understood in terms of pathology and mechanism. Zebrafish (Danio rerio) provide the opportunity to model photoreceptor diseases in a diurnal vertebrate with a cone-rich retina which develops many macular degeneration-like pathologies. Zebrafish undergo external development, allowing early-onset retinal diseases to be detected and studied, and many ophthalmic tools are available for zebrafish visual assessment during development and adulthood. There are numerous zebrafish models of photoreceptor disease, spanning the various types of photoreceptor disease (developmental, rod, cone, and mixed photoreceptor diseases) and genetic/molecular cause. In this review, we explore the features of zebrafish that make them uniquely poised to model cone diseases, summarize the established zebrafish models of inherited photoreceptor disease, and discuss how disease in these models compares to the human presentation, where applicable. Further, we highlight the contributions of these zebrafish models to our understanding of photoreceptor biology and disease, and discuss future directions for utilising and investigating these diverse models.
Non-protective immune imprint underlies failure of Staphylococcus aureus IsdB vaccine
Authors: Chih-Ming Tsai, J.R. Caldera, Irshad A. Hajam, Austin W.T. Chiang, Chih-Hsiung Tsai, Haining Li, María Lázaro Díez, Cesia Gonzalez, Desmond Trieu, Gislâine A. Martins, David M. Underhill, Moshe Arditi, Nathan E. Lewis, George Y. Liu
Journal: Cell Host & Microbe (2022)

Humans frequently encounter Staphylococcus aureus (SA) throughout life. Animal studies have yielded SA candidate vaccines, yet all human SA vaccine trials have failed. One notable vaccine "failure" targeted IsdB, critical for host iron acquisition. We explored a fundamental difference between humans and laboratory animals-natural SA exposure. Recapitulating the failed phase III IsdB vaccine trial, mice previously infected with SA do not mount protective antibody responses to vaccination, unlike naive animals. Non-protective antibodies exhibit increased α2,3 sialylation that blunts opsonophagocytosis and preferentially targets a non-protective IsdB domain. IsdB vaccination of SA-infected mice recalls non-neutralizing humoral responses, further reducing vaccine efficacy through direct antibody competition. IsdB vaccine interference was overcome by immunization against the IsdB heme-binding domain. Purified human IsdB-specific antibodies also blunt IsdB passive immunization, and additional SA vaccines are susceptible to SA pre-exposure. Thus, failed anti-SA immunization trials could be explained by non-protective imprint from prior host-SA interaction.
Diagnosis and treatment of tuberculosis infection: can it contribute to achieving tuberculosis elimination?
Authors: Alberto Matteelli, Jan-Willem C. Alffenaar
Journal: European Respiratory Journal (2022)

The END tuberculosis (TB) strategy, launched in 2015, calls for elimination of TB, defined as an incidence of less than one case of the disease per million population [1]. For the first time ever, it broadens the concept of TB control and raises the profile of diagnosis and treatment of the pool of infected individuals from which future TB cases will be generated [2]. Currently, the World Health Organization (WHO) estimates 10 million incident cases per year [3], while the number of persons with the infection is estimated at 1.7 billion [4]. Although not contagious, people with M. tuberculosis infection represent the reservoir for future TB cases. To meet the TB elimination goal, it is imperative that such a reservoir will also be extinguished. Models predict that elimination of TB can be reached by 2050 and that diagnosis and treatment of tuberculosis infection (TBI) outperforms other interventions [5]. Management of tuberculosis infection needs to be strengthened to achieve the goal of tuberculosis elimination <https://bit.ly/37iYQfD>
Multiscale Hierarchical Architecture‐Based Bioactive Scaffolds for Versatile Tissue Engineering (Adv. Healthcare Mater. 13/2022)
Authors: Hongshi Ma, Chen Yang, Zhenjiang Ma, Xiaoyue Wei, Muhammad Rizwan Younis, Hanbo Wang, Wentao Li, Zhiyong Wang, Wenhao Wang, Yongxiang Luo, Peng Huang, Jinwu Wang
Journal: Advanced Healthcare Materials (2022)

Hydrogel Scaffolds In article number 2102837, Yongxiang Luo, Peng Huang, Jinwu Wang, and co-workers present a method for inducing controlled tumor angiogenesis by engineering the microenvironment. The interstitial flow direction regulates the direction of capillary sprouting, while the existence of lung fibroblasts affects the continuity and lumen formation of sprouted capillaries. The vascularized tumor model shows enhanced delivery of anticancer drugs and immune cells to the tumor spheroids through the perfusable vascular networks.
Correction: Mutant SETBP1 enhances NRAS-driven MAPK pathway activation to promote aggressive leukemia
Authors: Sarah A. Carratt, Theodore P. Braun, Cody Coblentz, Zachary Schonrock, Rowan Callahan, Brittany M. Curtiss, Lauren Maloney, Amy C. Foley, Julia E. Maxson
Journal: Leukemia (2022)
Immune complications and their management in inherited and acquired bleeding disorders
Authors: Valder R. Arruda, David Lillicrap, Roland W. Herzog
Journal: Blood (2022)

Disorders of coagulation, resulting in serious risks for bleeding, may be caused by autoantibody formation or by mutations in genes encoding coagulation factors. In the latter case, antidrug antibodies (ADAs) may form against the clotting factor protein drugs used in replacement therapy, as is well documented in the treatment of the X-linked disease hemophilia. Such neutralizing antibodies against factors VIII or IX substantially complicate treatment. Autoantibody formation against factor VIII leads to acquired hemophilia. Although rare, antibody formation may occur in the treatment of other clotting factor deficiencies (eg, against von Willebrand factor [VWF]). The main strategies that have emerged to address these immune responses include (1) clinical immune tolerance induction (ITI) protocols; (2) immune suppression therapies (ISTs); and (3) the development of drugs that can improve hemostasis while bypassing the antibodies against coagulation factors altogether (some of these nonfactor therapies/NFTs are antibody-based, but they are distinct from traditional immunotherapy as they do not target the immune system). Choice of immune or alternative therapy and criteria for selection of a specific regimen for inherited and autoimmune bleeding disorders are explained. ITI serves as an important proof of principle that antigen-specific immune tolerance can be achieved in humans through repeated antigen administration, even in the absence of immune suppression. Finally, novel immunotherapy approaches that are still in the preclinical phase, such as cellular (for instance, regulatory T cell [Treg]) immunotherapies, gene therapy, and oral antigen administration, are discussed.
Psychological and actual group formation: Conflict is neither necessary nor sufficient
Authors: Julia Elad-Strenger, Thomas Kessler
Journal: Behavioral and Brain Sciences (2022)

Abstract Conflict is neither necessary nor sufficient for the existence of groups. First, the existence of mutually supporting , rather than antagonistic, interactants is sufficient to constitute a “social group.” Second, conflict does not necessarily mark group boundaries but can also exist within an ingroup. Third, psychological representations of social groups do not only trace, but also perpetuate the existence of groups.